Polymeric articles comprising oxygen permeability enhancing particles

ABSTRACT

The present invention relates to a composition comprising a hydrogel polymer having less than 100% haze, and distributed therein an oxygen enhancing effective amount of oxygen permeable particles having an oxygen permeability of at least about 100 barrer, average particle size less than about 5000 nm.

RELATED APPLICATIONS

This application is a division of application Ser. No. 12/721,081 filedMar. 10, 2010 and claims priority of U.S. Provisional Patent ApplicationNo. 61/164,931 filed Mar. 31, 2009 and U.S. Provisional PatentApplication No. 61/252,279 filed Oct. 16, 2009.

FIELD OF THE INVENTION

The invention relates to polymeric articles comprising oxygenpermeability enhancing particles and processes for forming sucharticles.

BACKGROUND OF THE INVENTION

Polymeric materials displaying oxygen permeability are desirable for anumber of applications, including medical devices. One such applicationis contact lenses.

Gas permeable soft contact lenses (“GPSCL”) have been made fromconventional and silicone hydrogels. Conventional hydrogels have beenprepared from monomeric mixtures predominantly containing hydrophilicmonomers, such as 2-hydroxyethyl methacrylate (“HEMA”), N-vinylpyrrolidone (“NVP”) and vinyl alcohol. The oxygen permeability of theseconventional hydrogel materials relates to the water content of thematerials, and is typically below about 20-30 barrers. For contactlenses made of the conventional hydrogel materials, that level of oxygenpermeability is suitable for short-term wear of the contact lenses;however, that level of oxygen permeability may be insufficient tomaintain a healthy cornea during long-term wear of contact lenses (e.g.,30 days without removal).

Silicone hydrogels (SiH's) are also currently used as materials inGPSCLs. Silicone hydrogels have typically been prepared by polymerizingmixtures containing at least one silicone-containing monomer or reactivemacromer and at least one hydrophilic monomer. While this class of lensmaterial reduces the corneal edema and hyper-vasculature associated withconventional hydrogel lenses, they can be difficult to produce becausethe silicone components and the hydrophilic components are incompatible.Additional material improvements to protein uptake profiles, wettabilityand general comfort on the eye over extended periods of time are alsodesirable.

Silicone elastomer contact lenses have also been made. These lensesdisplayed good oxygen permeability, but had poor wettability andmechanical properties. Reinforced silica filler has been disclosed asimproving the physical properties of the silicone elastomers.

SUMMARY OF THE INVENTION

The present invention relates to a composition comprising a polymerhaving distributed therein an oxygen enhancing effective amount ofoxygen permeable particles having an oxygen permeability of at leastabout 100 barrer and an average particle size less than about 5000 nm.

DESCRIPTION OF THE FIGURES

FIG. 1 is a graph of Dk vs. concentration of silicon microparticles inthe polymer.

FIG. 2 is a graph of Dk vs. silicon content.

FIG. 3 is an SEM micrograph of an etafilcon-based lens containing 800 nmShin Etsu POSS/PDMS micro-particles

FIG. 4 is the Volume Distribution Histogram of Particle Sizes forSiME-OHmPDMS 20

FIG. 5 is the Volume Distribution Histogram of Particle Sizes forSiME-OHmPDMS 40

FIG. 6 is the Volume Distribution Histogram of Particle Sizes forSiME-OHmPDMS 60

FIG. 7 is the Volume Distribution Histogram of Particle Sizes forSiME-OHmPDMS 80

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

As used herein, a “medical device” is any article that is designed to beused while either in or on mammalian tissues or fluid. Examples of thesedevices include but are not limited to catheters, implants, stents, andophthalmic devices such as intraocular lenses and contact lenses. Thepreferred biomedical devices are ophthalmic devices, particularlycontact lenses, most particularly contact lenses made from hydrogels.

As used herein, the term “lens” refers to ophthalmic devices that residein or on the eye. These devices can provide optical correction, cosmeticenhancement, radiation reduction, including UV blocking and visiblelight or glare reduction, therapeutic effect, including wound healing,delivery of drugs or nutraceuticals, diagnostic evaluation ormonitoring, or any combination thereof. The term lens includes, but isnot limited to, soft contact lenses, hard contact lenses, intraocularlenses, overlay lenses, ocular inserts, and optical inserts.

A “reaction mixture” is the mixture of components, including, reactivecomponents, diluent (if used), initiators, crosslinkers and additives,which when subjected to polymer forming conditions form a polymer.

Reactive components are the components in the reaction mixture, whichupon polymerization, become a permanent part of the polymer, either viachemical bonding, entrapment or entanglement within the polymer matrix.For example, reactive monomers become part of the polymer viapolymerization, while non-reactive polymeric internal wetting agents,such as PVP, and the oxygen permeable particles of the presentinvention, became part of the polymer via physical entrapment. Thediluent (if used) and any additional processing aids, such as deblockingagents do not become part of the structure of the polymer and are notpart of the reactive components. The reaction mixtures of the presentinvention can be formed by any of the methods known by those skilled inthe art to be useful to form polymeric articles or devices, and includestirring, rolling, kneading and shaking.

As used herein “biocompatibility” and “biocompatible” means that thematerial in question does not cause any substantial negative responsewhen in contact with the desired biological system. For example when theoxygen permeable particles are incorporated into contact lenses theundesirable negative responses include stinging, inflammation,undesirable levels of protein and lipid uptake, ocular cell damage andother immunological responses.

A “hydrogel” polymer is a polymer capable of absorbing or imbibing atleast about 20 weight % water, in some embodiments at least about 30weight % water and in other embodiments at least about 40 weight %water.

Oxygen permeable particles have an oxygen permeability of at least about100 barrer, in some embodiments between about 100 and about 1000 barrer,and in other embodiments between about 300 and about 1000 barrers. Theoxygen permeable particles may also have oxygen permeabilities of atleast about 300, 400 or 500 barrers. The oxygen permeable particles ofthe present invention may be solid, or “filled” or may be hollow. Solidoxygen permeable particles may be formed from crosslinked polymers, forexample, fluorine containing polymers, polydialkylsiloxane polymers,self-assembled siloxanes and rigid materials such aspolytrimethylsilylpropyne and combinations thereof.

In one embodiment the oxygen permeable particles are non-reactive meansthat under the conditions of formation and use of the compositions ofthe present invention, the oxygen permeable particles do not covalentlybond to the polymer but may associate with the polymer via dipole-dipoleforces such as hydrogen bond or van der Waals forces. If the oxygenpermeable particles are encapsulated, either the oxygen permeableparticles do not covalently bond to the encapsulating material, theencapsulating material does not bond to the polymer or both. In oneembodiment the oxygen permeable particles are surface reactive to assistin dispersing and/or stabilizing the oxygen permeable particles in theselected reaction mixtures.

Potentially anionic or cationic means that the molecule has latentionicity. An example of a potentially anionic group is a carboxylate,and an example of a potentially cationic group is an amine, andparticularly a tertiary amine.

The oxygen permeable particles are selected so that they do notsubstantially degrade the optical properties of the polymer, includingcolor and clarity. This may be accomplished by controlling the particlesize, refractive index, chemical properties of the oxygen permeableparticles or any combination of the foregoing. The oxygen permeableparticles have a refractive index of within about 20% hydrated polymermatrix and in some embodiments within about 10% of the refractive indexof the hydrated polymer matrix. Other embodiments may employ oxygenpermeable particles with a refractive index within about 1% of thehydrated polymer matrix and in other embodiments still, less than 0.5%.In one embodiment, the oxygen permeable particles have an averageparticle size between about 200 and about 1000 nm and a refractive indexwithin about 10% of the refractive index of the hydrated polymer matrix.Oxygen permeable particles with a particle size of less than 200 nm, mayhave refractive indices which are within about 20% of the refractiveindex of said hydrated polymer matrix. In one embodiment, where thepolymer is a hydrogel suitable for making contact lenses, the refractiveindex of the oxygen permeable particle is between about 1.37 and about1.45. In one embodiment the refractive index of the hydrogel polymer isbetween about 1.39 and about 1.43 and the encapsulated oxygen permeableparticles have a refractive index within the ranges specified above.

In one embodiment, the oxygen permeable particles are incorporated intothe ophthalmic devices, and in one embodiment contact lenses in at leastone region outside the optic zone. The optic zone is the region throughwhich light is focused. In this embodiment larger particle sizes can betolerated without refractive index matching. Thus, contact lenses madeaccording to this embodiment may have average particle sizes of betweenabout 200 nm and 100 microns.

Solid Oxygen Permeable Particles

Solid oxygen permeable particles may be formed from materials includingcross-linked polymers containing silicones, fluorine, and combinationsthereof, oxygen permeable perovskite oxides, combinations thereof andthe like. Specific examples of silicone containing polymers includepolydimethylsiloxane (PDMS), cross-linked poly(dimethylsiloxane),poly((trimethyl silyl)propyne) and cross-linked poly(dimethylsiloxane)core and a polydimethylsiloxane/and a poly(silsesquioxane) (PDMS/POSS)core/shell shell available from Shin Etsu, Inc. (Japan) under the nameX-52-7030, and having an average size distribution of 800 nm with arange from 0.2-2000 nm. Examples of fluorine containing polymers includeamorphous fluoropolymers such as2,2-bis(trifluoromethyl)-4,5-difluoro-1,3-dioxole copolymers withtetrafluoroethylene (sold under the tradename TEFLON AF), fluorinatedPDMS, and fluorinated polynorbornene. Copolymers and mixtures containingthe foregoing may also be used, so long as the oxygen permeableparticles have oxygen permeabilities in the ranges disclosed herein. Inone embodiment, the solid oxygen permeable particle comprises at leastone inorganic material, such as metalloids such as boron nitrides, metaloxides, including iron oxide, aluminum oxide, titanium dioxide,zirconium oxide, metals, such as gold, transition metal sulfides, suchas ZnS and CdS, graphene, inorganic/organic hybrids such as whole shellmetal oxides coated with cellulose, Copolymers containing the foregoingand mixtures of any of the foregoing with any of the inorganic materialsmay also be used.

Suitable solid oxygen permeable particles have an average particle sizeless than 5000 nm, in some embodiments less than about 1000 nm, in someembodiments less than about 800 nm, in other embodiments less than about600 nm and in other embodiments still, less than about 200 nm.

Hollow Nanoparticles

Alternatively, the oxygen permeable particles may be hollow. Suitablehollow nanostructures have a rigid shell which is impermeable to waterand which encapsulates or encloses a gas-filled space. Hollownanostructures are permeable to gases such as oxygen and air, and havean oxygen permeability of at least about 200 barrer, in some embodimentsat least about 300 barrer, in some embodiments at least about 500barrer, and in other embodiments greater than about 1000 barrers. Thehollow nanostructures of the present invention are known by differentnames including nanostructures, nanoballoons, microcapsules, gasvesicles and microspheres. Any of these known nanostructures may beused, so long as they possess the characteristics described herein.Suitable nanostructures include synthetic hollow nanostructures and gasvesicles. Gas vesicles (or gas vesicle proteins) are naturally found inbacteria and have protein shells which enclose a gas filled space.Synthetic nanostructures comprise shells formed from polymers, metaloxides, metalloids, carbon and combinations thereof.

When the oxygen permeable particle is a hollow nanostructure, the hollownanostructures have a particle size, in the longest dimension, of lessthan 500, in some embodiments less than about 400 nm and in otherembodiments still, between about 10 and about 100 nm. In one embodimentthe hollow nanostructure have an average diameter of about 20 to about100 nm and a length of about 100 to about 500 nm. The nanostructures mayhave any closed, hollow structure, including cylindrical with closedends, spherical, ovoid, regular and irregular polyhedra, ellipsoids,cones, spheroids (which can be described by the lengths of their 3principal axes), and combinations thereof or irregularly shaped.Naturally occurring nanostructures, such as gas vesicles, are frequentlycylindrical with conical ends. Synthetic nanostructures may have anyshape, and in one embodiment are selected from cylindrical and sphericalstructures.

The shell of the hollow nanostructures is permeable to gases, andparticularly to oxygen, and to mixtures comprising oxygen, such as air.Gases such as oxygen and air freely move through the hollownanostructures of the present invention. The nanostructure shells of thepresent invention have oxygen permeabilities of at least about 5 barrer,in some embodiments of at least about 20 barrer. In one embodiment, theoxygen permeability of the shell is equal to or greater than the oxygenpermeability of the substrate polymer. However, because the shellthickness is relatively thin (less than about 10 nm, and in someembodiments between about 1 and about 5 nm) compared to the size of thenanostructure, relatively low oxygen permeabilities of the shellmaterials are still useful.

Because gases freely diffuse through the hollow nanostructures, andliquids (particularly water) do not, the shape of the nanostructures ismaintained by the rigidity of the materials used to form the shell. Theshell materials have a modulus of at least about 1 GPa, in someembodiments at least about 2 GPa, and in some embodiments between about2.5 GPa and about 3.5 GPa. Shapes which are known to be stable underpressure include spheres and cylinders, cones and spheroids (which canbe described by the lengths of their 3 principal axes), and combinationsthereof. In one embodiment that hollow nanostructure is a sphere, and inanother spheres having an average diameter of about 200 nm.

The structures may also include reinforcing structures such as ribs,reinforcing fillers, nanofibers, structural proteins, crosslinks (ionicor covalent) combinations thereof and the like.

The hollow nanostructures of the present invention retain their hollowstructure and do not collapse during the production, sterilization anduse of the articles in which they are incorporated. The maintenance orretention of the hollow nanostructure is characterized by a criticalpressure of a least about 0.05 MPa and in some embodiments between about0.1 MPa and about 0.3 MPa, and still other embodiments greater than 0.2MPa.

Generally the outer portion of the nanostructure is hydrophilic and theinner structure is water impermeable. This allows the nanostructure tobe readily dispersed in hydrophilic substrate polymers such ashydrogels, but prevents water from seeping into the gas filled cavity.The inner and outer structures of the nanostructure shell can be formedfrom separate layers, such as separate layers of polymers, proteins orother shell materials, or from a single amphiphilic material having itshydrophilic portion oriented outward, and the hydrophobic portionoriented toward the interior of the hollow nanostructure or towards aninner hydrophobic layer of the shell.

The hydrophilicity and water permeability of materials useful forforming the nanostructure may be characterized by the water permeabilitycoefficient at 25° C. and the surface tension. Hydrophilic materialssuitable for the outer structure of the shell have water permeabilitycoefficients greater than about 100 and surface tensions greater thanabout 40 dyne/cm at 20° C. Water impermeable materials for the innerstructure of the shell have water permeability coefficients at 25° C. ofless than about 10, and surface tensions of less than about 35 dyne/cmat 20° C. In some embodiments the hydrophilic materials display contactangles of less than about 80°, and the water impermeable materialsdisplay contact angles of greater than about 100° when measured usingthe Wilhelmy plate method and distilled, deionized water at roomtemperature. Water permeability coefficients for a number of polymersare reported in Polymer Handbook, 4th Edition by J. Brandrup, Immergut,E. H., Grulke, E. A., Bloch, D.

In one embodiment the hollow nanostructures are formed synthetically.Examples of suitable synthetic methods include physicochemical processeswhere the shell material is precipitated during solvent evaporation oradsorption with controlled electrostatic or chemical interactions toform the shell. On example of this method is disclosed in Nature Vol 367Jan. 20 1994. The hollow nanostructures may be formed by the phaseseparation via solvent evaporation of a polymer mixture of two or morepolymers. The interfacial tensions and evaporation rates are selectedsuch that a spherical droplet of one polymer becomes coated with auniform layer of the other as a result of the spreading equilibriabetween two fluids suspended as emulsified droplets in a solvent.

When different materials are used for the inner and outer portions ofthe nanostructure shell, the material from which the outer hydrophiliclayer is formed may be a polymer which can be crosslinked or polymerizedwith itself. Examples of such materials include homo and copolymers of2-hydroethyl methacrylate (HEMA), polyvinyl acetate, methacrylic acid,N-vinylpyrrolidone, N-vinyl acetamide, N-vinyl methyl acetamide, N,Ndimethyl acrylamide, acrylic acid, glycerol monomethacrylate, MPC(2-Methacryloyloxyethyl phosphorylcholine), methyl methacrylate,hydroxyethyl acrylate, N-(1,1-dimethyl-3-oxybutyl)acrylamide,polyethylene glycol monomethacrylate, polyethylene glycoldimethacrylate, 2-ethoxyethyl methacrylate, 2-methacryloxyethylphosphorylcholine, combinations thereof and the like. Other polymershaving the water permeation coefficients and surface tensions describedabove may also be used. Examples include polysaccharides, hydrophilicpolypeptides, polyesters, polyamides including nylons having repeatingcarbon sections of less than 4 carbon atoms, polyurethanes,proteoglycans, cellulose and hydrophobic backbone polymers which havehydrophilic side chains sufficient to provide the water permeationcoefficients and surface tensions described above, and combinationsthereof. Specific examples of polymers which may be used to form theouter shell include poly(acrylamide co-acrylic acid),poly(N-isopropylacrylamide), 2-hydroxymethacrylic ester containingpolymers and copolymers, polyvinyl alcohol polymers and copolymers andthe like. The polymers may have any structure, including linear,branched and brush structures. In one embodiment the outer shell isformed from a crosslinked polymer comprising at least one monomer usedto form the substrate.

Examples of materials from which an inner layer may be formed includehomopolymers and copolymers comprising polyorganosiloxanes (includingsilicone methacrylates), fluorine containing polymers, liposomes,hydrophobic polypeptides, polyesters, polyamides, polyurethanes,polystyrenes, polyanilines, polypyrroles, combinations thereof and thelike. Examples of suitable inorganic materials include oxygen permeableperovskite oxides, metalloids such as boron nitrides, metal oxides,including iron oxide, aluminum oxide, titanium dioxide, zirconium oxide,metals, such as gold, transition metal sulfides, such as ZnS and CdS,graphene, inorganic/organic hybrids such as whole shell metal oxidescoated with cellulose, polytetrafluoroethane, combinations thereof andthe like. Specific examples of silicone containing polymers includepolydimethylsiloxane (PDMS), cross-linked poly(dimethylsiloxane),poly(silsesquioxane), poly((trimethyl silyl)propyne). Examples offluorine containing polymers include amorphous fluoropolymers such as2,2-bis(trifluoromethyl)-4,5-difluoro-1,3-dioxole copolymers withtetrafluoroethylene (sold under the tradename TEFLON AF), fluorinatedPDMS, and fluorinated polynorbornene. Copolymers containing theforegoing and mixtures of any of the foregoing with any of the inorganicmaterials may also be used.

The inner layer material may include latent reactive groups such aspentafluoromethacrylate and N-acryloxysuccinimide. Suitable latentreactive groups are disclosed in US2004/0120982 and may be added to theinner layer of the shell to allow reaction between the inner and outerlayer materials. In another embodiment, the inner and outer shellmaterials have alternating charges, allowing the materials to associatevia charge interaction. Examples of such materials include carboxylicacid metal salts, carboxylic acid/quaternary ammonium salts, sulfonicacid metal salts, sulfonic acids/quaternary ammonium salts.

Alternatively, the shell can be formed from one or more zwitterionicmaterial, amphiphilic material, or combination thereof. Suitablezwitterionic and micellar materials are disclosed below. The amphiphilicmaterials are assembled such that the hydrophobic portion is oriented intoward the cavity of the nanostructure and the hydrophilic portion isoriented out toward the substrate. The amphiphilic material is thencrosslinked to provide a nanostructure having the desired size, shapeand modulus.

In another embodiment, the hollow nanostructures may be formed around aseed or template particle which is removed after at least part of thenanostructure is formed. In this embodiment, polymerization reactions,such as emulsion polymerization, microemulsion polymerization,suspension polymerization or liposome or micelle formation followed bycrosslinking may be used to form the shell layer(s). Suitable templatematerials include polymeric microspheres, water-in-oil emulsiondroplets, lyotropic phases exhibiting a mulitlamellar vesicularstructure. The seed or template may be removed by calcination or solventetching after the shell or at last one layer of the shell is formed.Examples of this synthetic method have been disclosed in “Graphene: APerfect Nanoballoon”, Leenaerts et al., Applied Physics Letters, 93,193107 (2008). Dept Physics, Univ. Antwerpen; “Growing Nanoballoons andNanotubes of Pure polymer from a Microcapsule”, Fei et al., Inst.Textiles, Macromol. Rapid Commun 29 1882-1886, (2008). The Hong KongPolytechnic University; “Silicone Nanocapsules Templated Inside theMembranes of Cationic Vesicles”, Kepczynski et al., Langmuir, 237314-7320, (2007). Jagiellonian Univ. Krakow Poland; “Encapsulation ofInorganic Particles with Nanostructured Cellulose”, Nelson and Deng,Macromol. Mater. Eng., 292 1158-1163, (2007). Georgia Tech.; “StablePolymeric Nanoballoons: Lyphilization and Rehydration of Cross-linkedLiposomes”, Liu and O'Brian, J. Am. Chemical Society, 124 6037-6042,(2002), Chemistry Dept. Univ. Arizona; “Nanoparticles and nanoballoonsof amorphous boron coated with crystalline boron nitride”, Appl. Phys.Lett. 79, 188 (2001); “Carbon Nanoballoon Produced by Thermal Treatmentof Arc Soot”, New diamond and Frontier Carbon Technology, 15 No 2(2005). Toyohashi University of Technology Japan; Fabrication ofCore-Shell Fe₃O₄/polypyrole and Hollow Polypyrole Microspheres, PolymerComposites 2009. Lu et al., Jilin University, China. These disclosuresare incorporated herein by reference.

Alternatively carbon hollow nanostructures may be formed via the thermaltreatment of arc soot at more than 2400° C. Macromol. Mat. Eng. 2007292, 1158-1163 “Encapsulation of Inorganic Particles with NanostructuredCellulose”.

In another embodiment, the nanostructures may be naturally occurring gasvesicles isolated from bacteria, such as from cyanobacteria (such asAnabaena and Microcystis, Ocillatoria and Calothrix), methogens andhalophiles. Naturally occurring gas vesicles may be isolated by knownmethods such as those disclosed in WO 98/21311, which is incorporated inits entirety by reference. Isolated naturally occurring nanostructuresmay be used “as-isolated” or may be coated or encapsulated as disclosedherein.

Encapsulation

The oxygen permeable particles (both solid and hollow) may beencapsulated prior to incorporation into the reactive mixture used tomake the polymer. This is particularly useful when either the core of asolid oxygen permeable particle or an inner layer of a hollownanostructure is made from a water impermeable material or anamphiphilic material.

As used in the present invention “encapsulated” means surrounding theoxygen permeable particles with another material or entrapping theoxygen permeable particle within another material. Suitable means ofencapsulating include coating the oxygen permeable particles, entrappingthe oxygen permeable compounds within another material, to form forexample a liposomal, micellar or polymeric structure around the oxygenpermeable particles, combinations thereof and the like. The oxygenpermeable particles may be encapsulated for a number of reasons. Forexample, oxygen permeable particles may be coated with a polymer toprevent them from causing an immunological response when incorporatedinto a medical device. In one embodiment the oxygen permeable particlesmay be encapsulated to change the properties of the particles, such as,for example, to make them more compatible with the components of thereactive mixture used to make the polymer. In another embodiment theparticles may be encapsulated to help maintain a desired particle size,to prevent or limit aggregation or to provide the final article withother desired properties, such as but not limited to refractive index,biocompatibility (including immunological response, protein or lipiduptake), combinations thereof and the like. For example, the oxygenpermeable particles may be encapsulated within a hydrophilic shell anddispersed within the reactive mixture. In addition to displayingimproved compatibility with a hydrophilic reaction mixture,encapsulation also prevents the formation of hydrophobic sites within alens formed from said reaction mixture. Hydrophobic sites may causeprotein denaturation and lens fouling. Other reasons for encapsulation,and benefits therefrom will be apparent to those of skill in the art.

In one embodiment the oxygen permeable particles may be dispersed orsuspended in the reactive mixture. The particles may be dispersed viaionic or steric forces, or a combination thereof. In one embodimentoxygen permeable particles form stable dispersions displaying particlesizes of less than about 1000 nm, which remain dispersed for at leastabout one hour, and in some embodiments at least about one day, and insome embodiments for a week or more. In one embodiment, the reactionmixture may further comprise at least one surface active agent may beadded. Suitable surface active agents are compatible with the reactivemixture and suspended or dispersed particles, and do not cause haze.Suitable surface active agents include small molecule surfactants,polymeric surfactants, amphiphilic copolymers, combinations thereof andthe like. Examples of suitable surface active agents include PEG-120Methyl Glucose Dioleate (DOE 120, commercially from Lubrizol), PVP,polyvinyl alcohol/polyvinyl acetate copolymers, amphiphilic statisticalor block copolymers such as silicone/PVP block copolymers,polyalkylmethacrylate/hydrophilic block copolymers, organoalkoxysilanessuch as 3-aminopropyltriethoxysilane (APS), methyl-triethoxysilane(MTS), phenyl-trimethoxysilane (PTS), vinyl-triethoxysilane (VTS), and3-glycidoxypropyltrimethoxysilane (GPS), silicone macromers havingmolecular weights greater than about 10,000 and comprising groups whichincrease viscosity, such as hydrogen bonding groups, such as but notlimited to hydroxyl groups and urethane groups and mixtures thereof.

Where the dispersing agent is a polymer, it can have a range ofmolecular weights. Molecular weights from about 1000 up to severalmillion may be used. The upper limit is bounded only by the solubilityof the dispersing agent in the reactive mixture.

When a dispersing agent is used, the dispersing agent may be present inamounts between about 0.001% to about 40 weight %, based upon the weight% of all components in the reactive mixture. In some embodiments thedispersing agent may be present in amounts between about 0.01 weight %and about 30 weight % and in other embodiments between about 0.1 weight% and about 30 weight %. In some embodiments, the dispersing agent isalso a reactive component used to form the polymeric article, such aswhere a contact lens comprising polyvinyl alcohol is produced. In theseembodiments the amount of dispersing agent used may be up to about 90weight % and in some embodiments up to about 100 weight % based upon theweight % of all components in the reactive mixture.

In one embodiment the oxygen permeable particles are coated with acoating composition. Suitable coating compositions may be selected toprovide any of the features described above. For example, wherecompatibility with a conventional hydrogel reactive mixture is desired,suitable coating compositions include anionic, potentially anionic,cationic, potentially cationic, zwitterionic and polar neutral coatingcompositions, combinations thereof and the like. Examples of anionic andpotentially anionic polymers which may be used as coating materialsinclude, polyacrylic acid, hyaluronic acid, dextran sulfate, alginates,copolymers and mixtures thereof and the like.

Examples of cationic and potentially cationic polymers includepoly(diallyldimethylammonium chloride) (PDADMAC), chitosan, poly(quats),poly(amines), poly(pyridines), copolymers and mixtures thereof and thelike.

Examples of zwitterionic polymers include poly(sulfobetaines),poly(carboxybetaines), poly(phosphobetaines), copolymers thereof and thelike. Specific examples of zwitterionic polymers includepoly(3-[N-(2-acrylamidoethyl)dimethylammonio]propanesulfonate)poly(3-[N-(2-methylacrylamidoethyl)dimethylammonio]propanesulfonate),poly(3-[N-(2-methacryloxyethyl)dimethylammonio]propanesulfonate,poly(3-(N,N-dimethyl-N-(4-vinyl-phenyl)-ammonio)propanesulfonate,poly(3-[N-(2-acrylamidoethyl)dimethylammonio]propionate),poly(3-[N-(2-methylacrylamidoethyl)dimethylammonio]propionate),poly(3-[N-(2-methacryloxyethyl)dimethylammonio]propionte,poly(3-(N,N-dimethyl-N-(4-vinyl-phenyl)-ammonio)propionate, andpoly(2-methacryloyloxyethyl phosphorylcholine. In some embodiments,anionic and zwitterionic or cationic and zwitterionic coatingcompositions comprise the outermost layer. The oxygen permeableparticles may be coated with one or more layers.

Suitable methods for coating include 1) deposition of alternating layersof cationic/anionic polymers, polyacid/polybases, or polymeric hydrogendonor/acceptor species, 2) plasma treatment, 3) divergent and convergentgraft (co)polymerization via conventional or controlled radicalpolymerization, 4) simple chemical modification of the surface withsmall molecules, such as grafting, or 5) surface degradation by chemicalmeans, i.e. acid/base catalyzed hydrolysis, modification of the particlesurface via ion, x-ray, gamma ray, or electron bombardment. Othermodifications methods include oxidative plasma treatment and controlledgas plasma deposition.

In another embodiment the oxygen permeable particles are encapsulatedwithin a micelle. This can be accomplished by a variety of routes,including but not limited to 1) direct micellization/solubilization ofPDMS fluid to form an oil-in-water emulsion or micro-emulsion with asuitable surfactant system, 2) formation of an emulsion/micro-emulsionand subsequent curing of a reactive silicone, where the reactivesilicone could consist of, but is not limited to a silanol functionalpolydialkyl siloxane oligomer, 3) formation of an emulsion ormicro-emulsion and subsequent metal-catalyzed curing of reactivesilicones, where the reactive silicone could consist of, but is notlimited to a mixture of a vinyl- or allyl-functional polydialkylsiloxane oligomer and a hydride functional polydialkyl siloxaneoligomer, and 4) preparation of siloxy-containing latexes via emulsionor micro-emulsion free radical polymerization using vinyl siloxymacromers such as, but not limited to polydialkyl siloxanes, such asmPDMS (monomethacryloxypropyl terminated mono-n-butyl terminatedpolydimethylsiloxane) or OHmPDMS(mono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated, mono-butylterminated polydimethylsiloxane)), SiMAA DM(Methyl-bis(trimethylsilyloxy)-silyl-propylglycerol-dimethacrylate), orcombinations thereof. The above-mentionedsiloxy-emulsions/micro-emulsions may also be prepared directly in areactive monomer mixture with appropriate monomer and diluent selection.Particles formed via the above-mentioned emulsion/micro-emulsionprocesses can be further stabilized by incorporation of a cross-linkingagent during the curing process. Selection of cross-linking agentsdepends on the functionality of the reactive-silicone employed inparticle formation. Examples of silicone cross-linking agents are wellknown to those skilled in the art and include, but are not limited toSiMAA DM(Methyl-bis(trimethylsilyloxy)-silyl-propylglycerol-dimethacrylate),tetra-alkoxy silanes and poly-functional vinyl, allyl, or silyl-hydridemoieties with appropriate hydrosilylating metal catalysts.

Siloxy-emulsions/micro-emulsions may be formed from a variety ofsurfactant systems, including both ionic and non-ionic detergents.Surfactants that are commonly used in the preparation of latexes may beemployed and are obvious to those skilled in the art. Examples of saidsurfactants include, but are not limited to alkyl sulfates, alkylsulfonates, alkylbenzene sulfonates, fatty acids, alkyl ethoxylates,alkyl quaternary ammonium salts, alkyl glucocides, polysorbates, and allcombinations thereof.

Reactive surfactants may also be employed in the preparation of siliconemicroemulsion systems. Also known in the literature as “surfmers,” thesesurface-active compounds contain a reactive group at the hydrophobic orhydrophilic terminus and are capable of taking part in thepolymerization process, thereby incorporating themselves into finalpolymeric particle and eliminating or minimizing the need for surfactantremoval. Examples of such materials that may be used to form siliconemicroemulsion particles include but are not limited to allylpolyalkylene glycol ethers, vinyl polyalkylene glycol ethers, allylpolyalkylene glycol ether sulfates, methacrylic acid esters of alkylpolyethylene glycol ethers, and vinyl polyethylene glycol ethers. Theseagents may be used as a substitute for or in combination with theabove-mentioned standard emulsion polymerization surfactants.

In addition to lower molecular weight surfactants, polymeric surfactantsand emulsifying agents may also be used in the preparation ofsiloxy-emulsions/micro-emulsions. Examples of such polymeric surfactantsare well-known to those skilled in the art and include, but are notlimited to pluronic/polaxamer surfactants, (co)polymers of N-vinylpyrrolidone, copolymers of various hydrophobic monomers with vinylalcohol, poly(ethylene-co-maleic anhydride) and combinations there of.

Embodiments involving the preparation of siloxy-latexes via free radicalmicro-emulsion polymerization, using vinyl siloxy macromers, such as,but not limited to SiMAA2 DM, OHmPDMS, and/or mPDMS, or combinationsthereof, allow for the facile synthesis of high Dk particles withtunable compositions, and consequently, controlled structures andproperties. Generally, this embodiment involves a micro-emulsioncomposed of one or a combination of the above-mentioned surfactants inwater, at least one siloxy macromer, a cross-linking reactive monomer(such as SiMAA2 DM, EGDMA (ethylene glycol dimethacrylate) or DVB(divinylbenzene)), and a water-soluble free radical initiator. Dependingon choice of initiator, the polymerization may be initiated via thermal,photochemical, or redox pathways. In a more preferred embodiment, theratio of OHmPDMS to SiMAA2 DM may be varied to obtain final particleswith tailored physical properties, including but not limited todesirable refractive index values and increased particle stability.

In the above embodiment, “water-soluble free radical initiator” isdefined as any compound that, under specific conditions (i.e.temperature, light intensity and wavelength), generates one or multipleactive radical species. These compounds are well known to those skilledin the art. Examples of water-soluble free radical initiators that maybe employed within this embodiment include but are not limited to VA-044(2,2′-Azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride), V-50(2,2′-Azobis(2-methylpropionamidine)dihydrochloride), VA-057(2,2′-Azobis[N-(2-carboxyethyl)-2-methylpropionamidine]hydrate, VA-060(2,2′-Azobis{2-[1-(2-hydroxyethyl)-2-imidazolin-2-yl]propane}dihydrochloride),VA-061 (2,2′-Azobis[2-(2-imidazolin-2-yl)propane]), VA-067(2,2′-Azobis(1-imino-1-pyrrolidino-2-ethylpropane)dihydrochloride),VA-80 (2,2′-Azobis{2-methyl-N-[1,1-bis(hydroxymethyl)-2-hydroxyethyl]propionamide}),VA-086 (2,2′-Azobis[2-methyl-N-(2-hydroxyethyl)propionamide], VPE-0201(poly(ethylene glycol) macro initiator MW=2000 g/mole), VPE-0401(poly(ethylene glycol) macro initiator MW=4000 g/mole), VPE-0602(poly(ethylene glycol) macro initiator MW=6000 g/mole), potassiumpersulfate, and any water-soluble photo-initiator. The invention is notrestricted to the use of water-soluble free radical initiators.Micro-emulsion systems may be prepared with conventional oil solubleinitiators.

In an additional preferred embodiment, the choice of water-soluble freeradical initiator may dictate the final properties of the particlesgenerated by emulsion/micro-emulsion polymerization. For example, if ahydroxyl- or PEG-functional initiator is employed in the polymerization,the surface properties of the final siloxy-latex may be modified,leading to controlled surface features, such as but not limited to,increased surface polarity, hydrophilicity, and consequently,biocompatibility.

Once formed, the oxygen permeable polymeric particles may covalentlybond to, may associate with, or may be physically entrapped within theirstabilizing surfactants. The particles may have a core/shell structure,containing the high Dk material in the core and the stabilizingsurfactants and other stabilizing moieties in the shell. Once formed themicelle may covalently bond to the hydrogel polymer, may associate withthe hydrogel polymer, or may be physically entrapped within the hydrogelpolymer. The micelle may have a core/shell structure. Suitablecompositions for forming micellar coatings may be selected to provideany of the features described above. For example, where compatibilitywith a conventional hydrogel reactive mixture is desired, suitablemicelle compositions include that yield in the final particle, ananionic, cationic, zwitterionic, or polar-neutral micelle surface. Suchmoieties on the surface of micelle particles can be introduced byemploying a silicone-reactive capping agent or surfactant during theemulsion/micro-emulsion process.

Any of the anionic, cationic or zwitterionic polymers disclosed above ascoating compounds may be used in forming micellar coatings, so long asone end comprises the cationic, zwitterionic or anionic groups disclosedabove, and the other end is compatible with said oxygen permeableparticle. Examples of moieties which may be included at the hydrophobicterminus include alkoxy silanes, polychloro-silanes, vinyl silanes,polyfunctional allyl moieties, and polsilyl-hydrides, etc.), analiphatic linker (typically propyl or butyl), and the like. Monomers andoligomers may also be used to form the micellar coatings of the presentinvention. Specific examples include alkyl benzene sulfonate and alkylethoxylate made by the methods described in IN 2003KO00640 by WackerMetroark Chemicals Ltd. Other patents involving silicone MEpolymerizations include U.S. Pat. No. 5,661,215, and U.S. Pat. No.6,316,541.

Suitable methods for forming a micellar coating include those that yieldin the final particle, an anionic, cationic, zwitterionic, orpolar-neutral surface. Such moieties on the surface of micelle particlescan be introduced by employing a silicone-reactive capping agent orsurfactant during the emulsion process. The capping agents are alsosurface-active and include a hydrophobic silicone-reactive moiety at oneterminus (including, but not limited to alkoxy silanes,polychloro-silanes, vinyl silanes, polyfunctional allyl moieties, andpolsilyl-hydrides, etc.), an aliphatic linker (typically propyl orbutyl), and the desired polar or ionic group at the other terminus. Thesurface chemistry of the micelle particles can be easily manipulated byappropriate selection of capping agent in combinations thereof and thelike.

Generally an emulsion is formed by mixing the selected surfactant in asuitable solvent above the critical micelle concentration, andpreferably in concentrations greater than about 10 weight % and in someembodiments between about 15 and about 25 weight % surfactant, and insome embodiments between about 15 to about 20 weight %. Both emulsionsand microemulsions can be used in the present invention, and whereveremulsions are disclosed, microemulsions may also be formed dependingupon the particles and surfactants selected. The emulsion is heated andthe oxygen permeable particles added. In some embodiments crosslinkingagents may be added to form crosslinked micelles.

In another embodiment the oxygen permeable particles are encapsulatedinto liposomes. Suitable compositions may be selected to provide any ofthe features described above. For example, where compatibility with aconventional hydrogel reactive mixture is desired, phospholipids andother liposome-forming compounds may be employed. Suitable liposomeforming compounds may include, but are not limited to DSPC(distearoylphosphatidylcholine), HSPC (hydrogentated soyphosphatidylcholine), and poly(ethylene glycol) conjugates withcholesterol, lipids, and phospholipids, combinations thereof, and thelike.

Suitable methods for forming liposomes include known methods, such asbut not limited to mixing the desired components, sonication, membraneextrusion and the like.

Examples of encapsulated solid oxygen permeable particles includecross-linked poly(dimethylsiloxane) core and a poly(silsesquioxane)shell prepared by Shin Etsu, Inc. (Japan) sold as X-52-7030, and havingan average size distribution of 800 nm with a range from 0.2-2000 nm,dimethicone/vinyl dimethicone crosspolymer with silica treated coating,sold by Dow Corning as 9701 Cosmetic Powder.

The oxygen permeable particles may be incorporated into the hydrogelpolymers of the present invention in an oxygen permeable enhancingeffective amount. As used herein, an “oxygen permeable enhancingeffective amount” is an amount effective to increase the oxygenpermeability of the polymer by at least about 10%, at least about 25%,and in some embodiments at least about 50%, and in other embodiments,greater than 100%, compared to the oxygen permeability of the hydrogelpolymer having no oxygen permeable particles. In some embodiments thecompositions of the present invention comprise oxygen permeabilities ofat least 25 barrer, at least about 40 barrers, in some embodiments atleast about 60 barrers, and in other embodiments at least about 80barrers and in other embodiments at least about 100 barrers.

The amount of oxygen permeable particles to be added to a reactivemixture can be readily determined by the desired oxygen permeability forthe composition and the oxygen permeability for the polymer without anyoxygen permeable particles. This may be readily done by making films ofthe polymers having different concentrations of the oxygen permeableparticles, measuring the Dk of the films and interpolating to thedesired oxygen permeability target to a concentration for the oxygenpermeable particles of 100%. Additionally, for hollow nanostructures,the amount of nanostructures to be added to a reactive mixture can bereadily determined by the target oxygen permeability of the systemutilizing known permeability theory as described in Journal ofBiotechnology 77 (2000) 151-156 “Evaluation of oxygen permeability ofgas vesicles from cyanobacterium Anabaena flos-aquae”.

The oxygen permeability of the encapsulated oxygen permeable particleswill be dependent upon the properties of both the oxygen permeableparticle and the encapsulating material, including, but not limited toparticle size, surface area of the encapsulated particle, surfacecomposition, thickness of the encapsulating material, degree ofcross-linking in the core and shell.

For example, in one embodiment, where the hydrogel polymer is acopolymer hydroxyethyl methacrylate (HEMA) and about 2 weight %methacrylic acid (MAA), (which has an oxygen permeability of about 20barrers), and the particles of PDMS (which has an oxygen permeability ofabout 600 barrers) are used as the oxygen permeable particle, the oxygenpermeable particles may be added in amounts of at least about 15 weight%, and in some embodiments between about 20 and about 70 weight %.

The oxygen permeable particles may be added in amounts which areinsufficient to undesirably impact other properties of the resultingcomposition. For example, where the composition will be used to makearticles which must be clear to be useful, such as contact lenses, thepolymer should be free from visible haze at the desired thickness of thearticle. In these embodiments, the polymer displays a % haze of lessabout 15%, in some embodiments less about 10%, and in others less thanabout 5% using the method described below. In another embodiment, thearticle is a contact lens, and the oxygen permeable particles areprimarily incorporated outside the optic zone. This allows loadings ofparticles which have particles, particle concentrations or both whichcause haze in the resulting lens.

It is a benefit of the present invention that the oxygen permeableparticles may be added to the reactive mixtures used to makeconventional hydrogels. Conventional hydrogels are well known andinclude homo and copolymers of polyHEMA and polyvinyl alcohol. Suitablecomonomers include methacrylic acid, N-vinylpyrrolidone, N-vinylacetamide, N-vinyl methyl acetamide, N,N dimethyl acrylamide, acrylicacid, glycerol monomethacrylate, MPC (2-Methacryloyloxyethylphosphorylcholine)), methyl methacrylate, hydroxyethyl acrylate,N-(1,1-dimethyl-3-oxybutyl)acrylamide, polyethylene glycolmonomethacrylate, polyethylene glycol dimethacrylate, 2-ethoxyethylmethacrylate, 2-methacryloxyethyl phosphorylcholine combinations thereofand the like. Homo and copolymers of polyHEMA include etafilcon,polymacon, vifilcon, bufilcon, crofilcon, genfilcon, hioxifilcon,lenefilcon, methafilcon, ocufilcon, perfilcon, surfilcon, tetrafilcon.Homo and copolymers of polyvinyl alcohol may also be used, includingatlafilcon, and nelfilcon. Homo and copolymers of methyl methacrylateand hydrophilic monomers such as N,N-dimethyl methacrylamide or N-vinylpyrrolidone, such as lidofilcon, may also be used. However, the oxygenpermeable particles may be used to increase the oxygen permeability ofany hydrogel formulation, including silicone hydrogels such as but notlimited to balafilcon, lotrafilcon, aquafilcon, senofilcon, galyfilcon,narafilcon, comfilcon, oxyfilcon, siloxyfilcon and the like. When a USANname is listed it includes all variations under the same name. Forexamples, lotrafilcon includes both lotrafilcon A and B.

The oxygen permeable particles of the present invention may be addeddirectly to the reaction mixture used to form the hydrogel polymer ormay be soaked or imbibed into the hydrogel polymer post cure.

The reactive components and oxygen permeable particles are mixedtogether to form the reactive mixture. The reactive mixture mayoptionally include diluents to help with processing or provide improvedcompatibility. Suitable diluents are known in art and may be selectedbased upon the polymer which is selected. For example, suitable diluentsfor conventional hydrogels include organic solvents, water or mixtureshereof. In one embodiment when a conventional hydrogel is selected asthe polymer, organic solvents such as alcohols, diols, triols, polyolsand polyalkylene glycols may be used. Examples include but are notlimited to glycerin, diols such as ethylene glycol or diethylene glycol;boris acid esters of polyols such as those described in U.S. Pat. Nos.4,680,336; 4,889,664 and 5,039,459; polyvinylpyrrolidone; ethoxylatedalkyl glucoside; ethoxylated bisphenol A; polyethylene glycol; mixturesof propoxylated and ethoxylated alkyl glucoside; single phase mixture ofethoxylated or propoxylated alkyl glucoside and C₂₋₁₂ dihydric alcohol;adducts of ε-caprolactone and C₂₋₆ alkanediols and triols; ethoxylatedC₃₋₆ alkanetriol; and mixtures of these as described in U.S. Pat. Nos.5,457,140; 5,490,059, 5,490,960; 5,498,379; 5,594,043; 5,684,058;5,736,409; 5,910,519. Diluents can also be selected from the grouphaving a combination of a defined viscosity and Hanson cohesionparameter as described in U.S. Pat. No. 4,680,336.

It may also be desirable to include one or more cross-linking agents,also referred to as cross-linking monomers, in the reaction mixture,such as ethylene glycol dimethacrylate (“EGDMA”), trimethylolpropanetrimethacrylate (“TMPTMA”), glycerol trimethacrylate, polyethyleneglycol dimethacrylate (wherein the polyethylene glycol preferably has amolecular weight up to, e.g., about 5000), and other polyacrylate andpolymethacrylate esters, such as the end-capped polyoxyethylene polyolsdescribed above containing two or more terminal methacrylate moieties.The cross-linking agents are used in the usual amounts, e.g., up toabout 2 weight % of reactive components in the reaction mixture.Alternatively, if any of the monomer components act as a cross-linkingagent, the addition of a separate crosslinking agent to the reactionmixture is optional. Examples of hydrophilic monomers that can act asthe crosslinking agent and when present do not require the addition ofan additional crosslinking agent to the reaction mixture includepolyoxyethylene polyols containing two or more terminal methacrylatemoieties.

The reactive mixture may contain additional components such as, but notlimited to, UV absorbers, medicinal agents, antimicrobial compounds,reactive tints, pigments, copolymerizable and nonpolymerizable dyes,release agents and combinations thereof.

A polymerization initiator may also be included in the reaction mixture.Polymerization initiators include compounds such as lauryl peroxide,benzoyl peroxide, isopropyl percarbonate, azobisisobutyronitrile, andthe like, that generate free radicals at moderately elevatedtemperatures, and photoinitiator systems such as aromatic alpha-hydroxyketones, alkoxyoxybenzoins, acetophenones, acylphosphine oxides,bisacylphosphine oxides, and a tertiary amine plus a diketone, mixturesthereof and the like. Illustrative examples of photoinitiators are1-hydroxycyclohexyl phenyl ketone,2-hydroxy-2-methyl-1-phenyl-propan-1-one,bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide(DMBAPO), bis(2,4,6-trimethylbenzoyl)-phenyl phosphineoxide (Irgacure819), 2,4,6-trimethylbenzyldiphenyl phosphine oxide and2,4,6-trimethylbenzoyl diphenylphosphine oxide, benzoin methyl ester anda combination of camphorquinone and ethyl 4-(N,N-dimethylamino)benzoate.Commercially available visible light initiator systems include Irgacure819, Irgacure 1700, Irgacure 1800, Irgacure 819, Irgacure 1850 (all fromCiba Specialty Chemicals) and Lucirin TPO initiator (available fromBASF). Commercially available UV photoinitiators include Darocur 1173and Darocur 2959 (Ciba Specialty Chemicals). These and otherphotoinitiators which may be used are disclosed in Volume III,Photoinitiators for Free Radical Cationic & Anionic Photopolymerization,2^(nd) Edition by J. V. Crivello & K. Dietliker; edited by G. Bradley;John Wiley and Sons; New York; 1998, which is incorporated herein byreference. The initiator is used in the reaction mixture in effectiveamounts to initiate photopolymerization of the reaction mixture, e.g.,from about 0.1 to about 2 parts by weight per 100 parts of reactivemonomer. Polymerization of the reaction mixture can be initiated usingthe appropriate choice of heat or visible or ultraviolet light or othermeans depending on the polymerization initiator used. Alternatively,initiation can be conducted without a photoinitiator using, for example,e-beam. However, in one embodiment when a photoinitiator is used,preferred initiators induce bisacylphosphine oxides, such asbis(2,4,6-trimethylbenzoyl)-phenyl phosphine oxide (Irgacure 819®) or acombination of 1-hydroxycyclohexyl phenyl ketone andbis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide(DMBAPO), and a preferred method of polymerization initiation is visiblelight. A preferred is bis(2,4,6-trimethylbenzoyl)-phenyl phosphine oxide(Irgacure 819®).

Articles, such as biomedical devices, and in some embodiments ophthalmicdevices, may be prepared by mixing reactive components and thediluent(s), if used, with a polymerization initiator and curing byappropriate conditions to form a product that can be subsequently formedinto the appropriate shape by lathing, cutting and the like.Alternatively, the reaction mixture may be placed in a mold having theshape of the desired article and subsequently cured into the desiredarticle.

For example, where the reactive mixture is used to form a contact lens,any of the known processes for curing the reaction mixture in theproduction of contact lenses, including spincasting and static casting,may be used. Spincasting methods are disclosed in U.S. Pat. Nos.3,408,429 and 3,660,545, and static casting methods are disclosed inU.S. Pat. Nos. 4,113,224 and 4,197,266. In one embodiment, the methodfor producing contact lenses comprising the polymer of this invention isby the direct molding of the reaction mixture, which is economical, andenables precise control over the final shape of the hydrated lens. Forthis method, the reaction mixture is placed in a mold having the shapeof the final desired lens, and the reaction mixture is subjected toconditions whereby the reactive components polymerize, to therebyproduce a polymer/diluent mixture in the shape of the final desiredlens.

The compositions of the present invention have a balance of propertieswhich makes them particularly useful. In one embodiment, where thecompositions are used to make lenses, and particularly contact lenses,such properties include clarity, water content, oxygen permeability andcontact angle. Thus, in one embodiment, the biomedical devices arecontact lenses having a water content of greater than about 20%, and insome embodiments greater than about 30%.

As used herein clarity means substantially free from visible haze. Clearlenses have a haze value of less than about 150%, more preferably lessthan about 100% compared to a CSI lens.

The use of conventional hydrogels as the polymer provides additionalbenefits to resulting articles such as contact lenses, including contactangles below about 100°, and modulus below about 100 psi.

In some embodiments, contact lenses formed from the compositions of thepresent invention have average contact angles (advancing) which are lessthan about 80°, less than about 75° and in some embodiments less thanabout 70°. In some embodiments the articles of the present inventionhave combinations of the above described oxygen permeability, watercontent and contact angle. All combinations of the above ranges aredeemed to be within the present invention.

Haze Measurement

As used herein clarity means substantially free from visible haze.Clarity may be measured via % haze which is calculated fromtransmittance. Transmittance may be measured via ASTM D1003 using anintegrating sphere hazemeter. The test is conducted by taking fourdifferent consecutive readings and measuring the photocell output asfollows

T₁=specimen and light trap out of position, reflectance standard inposition

T₂=specimen and reflectance standard in position, light trap out ofposition

T₃=light trap in position, specimen and reflectance standard out ofposition

T₄=specimen and light trap in position, reflectance standard out ofposition

The quantities represented in each reading are incident light, totallight transmitted by specimen, light scattered by instrument, and lightscattered by instrument and specimen, respectively.

Total transmittance T_(t and) diffuse transmittance T_(d) are calculatedas followsT _(t) =T ₂ /T ₁T _(d) =[T ₄ −T ₃(T ₂ /T ₁)]/T ₁

The percentage of haze is calculated as followsHaze percent=T _(d) /T _(t)×100Water Content

The water content of contact lenses was measured as follows: Three setsof three lenses are allowed to sit in packing solution for 24 hours.Each lens is blotted with damp wipes and weighed. The lenses are driedat 60° C. for four hours at a pressure of 0.4 inches Hg or less. Thedried lenses are weighed. The water content is calculated as follows:

${\%\mspace{14mu}{water}\mspace{14mu}{content}} = {\frac{\left( {{{wet}\mspace{14mu}{weight}} - {{dry}\mspace{14mu}{weight}}} \right)}{{wet}\mspace{14mu}{weight}} \times 100}$

The average and standard deviation of the water content are calculatedfor the samples and are reported.

Modulus

Modulus is measured by using the crosshead of a constant rate ofmovement type tensile testing machine equipped with a load cell that islowered to the initial gauge height. A suitable testing machine includesan Instron model 1122. A dog-bone shaped sample from −1.00 lenses havinga 0.522 inch length, 0.276 inch “ear” width and 0.213 inch “neck” widthis loaded into the grips and elongated at a constant rate of strain of 2in/min. until it breaks. The initial gauge length of the sample (Lo) andsample length at break (Lf) are measured. Twelve specimens of eachcomposition are measured and the average is reported. Percent elongationis =[(Lf−Lo)/Lo]×100. Tensile modulus is measured at the initial linearportion of the stress/strain curve.

Advancing Contact Angle

The advancing contact angle was measured using −1.00 power lenses asfollows. Four samples from each set were prepared by cutting out acenter strip from the lens approximately 5 mm in width and equilibratedin packing solution. The wetting force between the lens surface andborate buffered saline is measured at 23° C. using a Wilhelmymicrobalance while the sample is being immersed into or pulled out ofthe saline. The following equation is usedF=2γp cos θ or θ=cos⁻¹(F/2γp)where F is the wetting force, γ is the surface tension of the probeliquid, p is the perimeter of the sample at the meniscus and θ is thecontact angle. The advancing contact angle is obtained from the portionof the wetting experiment where the sample is being immersed into thepacking solution. Each sample was cycled four times and the results wereaveraged to obtain the advancing contact angles for the lens.Oxygen Permeability (Dk)

The Dk is measured as follows. Lenses are positioned on a polarographicoxygen sensor consisting of a 4 mm diameter gold cathode and a silverring anode then covered on the upper side with a mesh support. The lensis exposed to an atmosphere of humidified 2.1% O₂. The oxygen thatdiffuses through the lens is measured by the sensor. Lenses are eitherstacked on top of each other to increase the thickness or a thicker lensis used. The L/Dk of 4 samples with significantly different thicknessvalues are measured and plotted against the thickness. The inverse ofthe regressed slope is the Dk of the sample. The reference values arethose measured on commercially available contact lenses using thismethod. Balafilcon A lenses (−1.00) available from Bausch & Lomb give ameasurement of approx. 79 barrer. Etafilcon lenses give a measurement of20 to 25 barrer. (1 barrer=10⁻¹⁰ (cm³ of gas×cm²)/(cm³ of polymer×sec×cmHg)).

Si Content Via Neutron Activation

Si content was measured via neutron activation. All samples, standards,and quality controls are irradiated for 15 seconds, allowed to decay for120 seconds and counted for 300 seconds. The concentration of silicon isdetermined by measuring the 1779 keV gamma-ray from the decay of 28Al(t1/2=2.24 minutes). The 28Al is produced via the (n,p) reaction on28Si. Three geometrically equivalent silicon standards are analyzed withthe sample set. The standards are prepared by spiking paper pulp withsilicon from a 10.00±0.05 mg/mL certified solution standard (High PurityStandards). The results are blank corrected for the 28Al signal from theblank high-density polyethylene sample irradiation vial. NIST SRM 1066aOctaphenylcyclotetrasiloxane is co-analyzed with the samples as aquality control check for the analysis. The certified siliconconcentration in this SRM is 14.14±0.07 Wt. % Si. The average value forthe analysis of three 10 mg aliquots of the SRM was 14.63±0.70 Wt. % Si.

Surface Roughness

Surface roughness was measured via AFM using a Digital InstrumentsNanoscope, a scan size of 20 μm and a scan rate of 7.181 Hz. For eachsample 256 scans were processed and the data scale employed was 1000 μm.The engage X and Y positions were −19783.4 and −42151.3 μm,respectively.

Scanning Electron Microscopy of Lenses

SEM Surface Characterization:

Surface images were captured from all samples on both the concave andconvex surfaces at three locations (left, middle and right). The imagingwas performed using an FEI Quanta Environmental SEM using anaccelerating voltage of 25 kV and 5 nA of beam current at 5000×magnification for all locations in SE and BSE imaging modes.

SEM Profile Characterization:

Profile (cross-section) images were captured using the same beamconditions as the surface images. Since the entire cross section of thelens could not be imaged at 5 k× magnification creating mosaics of theimages was necessary to view the entire cross-section of each lens.Images were captured in serial at 5 k× magnification starting near theconcave side of the lens (top), then stepped frame by frame through thelens until the convex edge of the lens was eventually imaged. Theindividual images were then merged together using Photoshop.

The Examples below further describe this invention, but do not limit theinvention. They are meant only to suggest a method of practicing theinvention. Those knowledgeable in the field of contact lenses as well asother specialties may find other methods of practicing the invention.However, those methods are deemed to be within the scope of thisinvention.

Some of the materials employed in the Examples are identified asfollows:

-   BAGE: Boric acid glycerol ester-   DBS: N-Dodecylbenzenesulfonic acid, from Sigma Aldrich-   HEMA: 2-hydroxyethyl methacrylate (99% purity)-   MAA: methacrylic acid (99% purity)-   OHmPDMS: mono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated,    mono-butyl terminated polydimethylsiloxane), (612 molecular weight),    DSM Polymer Technology Group-   SiMAA DM:    Methyl-bis(trimethylsilyloxy)-silyl-propylglycerol-dimethacrylate,    DSM Polymer Technology Group, made according to Example Preparation    in US US2005/0255231-   Si microparticle: a cross-linked poly(dimethylsiloxane) core and a    poly(silsesquioxane) shell (Shin Etsu, Inc. (Japan), X-52-7030, with    an average size distribution of 800 nm with a range from 0.2-2000    nm, as determined by the manufacturer via SEM).

Examples 1-11

Monomer mix comprising 94.90% HEMA, 1.94% MAA, 0.95% Norbloc, 1.33%Irgacure 1700, 0.77% EGDMA, 0.09% TMPTMA, and 0.02% Blue HEMA (w/w) inBAGE diluent (52:48 monomer:diluent) herein referred to as reactivemonomer mix (RMM) was prepared and used for Examples 1-11.

In the preparation of examples 1-10 the desired mass of Simicroparticles was added to an amber scintillation vial followed byaddition of etafilcon RMM (10 g). The scintillation vial was capped androlled for 2 hours prior to being degassed in vacuo (10 minutes) andused to prepare lenses. Levels of microparticles and RMM employed foreach formulation are listed in Table 1, below. Lenses were then preparedfor each example by dosing each Si microparticle monomer mix intoseparate front curves via pipette.

Example 11 in Table 1 was prepared by suspending half of the mass of themicroparticles required in 2.4 g ethylene glycol and the other half in5.2 g of monomer mix without BAGE. The mixture was then further dilutedwith BAGE and homogenized via high-shear mechanical mixing. Theresulting monomer mix was degassed for 10 minutes in vacuo. The highviscosity of Example 11 required that it be dosed into the front-curvesvia a pressurized syringe.

All lenses were prepared at −1.0 power using Zeonor (Zeon Chemical)front/back curves. Curing was carried-out in an N₂-purged glove box at50° C. for 10 minutes under a TL03 lamp (400 nm) at an intensity of 3.4mW/cm². Lenses were demolded and released in a deionized water-bath at90° C. prior to being stored in Borate Buffered Saline Solution inindividual crimp-sealed, glass vials. All lenses were sterilized at 121°C. for 30 minutes in an autoclave prior to analysis.

TABLE 1 Reactive Si MP Diluent monomer % Si MP_(theo) % Si_(Theo) Ex #mass (g) mass(g) (g) in Lens in Lens 1 0.000 4.8 5.2 0.0 0.0 2 0.125 4.85.2 2.4 0.9 3 0.250 4.8 5.2 4.6 1.7 4 0.500 4.8 5.2 8.8 3.3 5 0.750 4.85.2 12.6 4.8 6 1.000 4.8 5.2 16.1 6.1 7 1.250 4.8 5.2 19.4 7.4 8 1.5004.8 5.2 22.4 8.5 9 1.750 4.8 5.2 25.2 9.6 10 2.800 4.8 5.2 35.0 13.3 1115.600 0.0 5.2 75.0 28.5

The Dk, water-content, and Si content were measured for each set oflenses.

The results for each mixture are listed in Table 2 below. It is readilyapparent from the data that as the level of silicone microparticles isincreased from 0% to 64.3%, the resulting lens Dk increases from 20 to76 units. FIG. 1 is a graph of Dk versus silicone microparticleconcentration in the final lens. FIG. 1, shows a positive, non-linearpolynomial trend.

When Dk is plotted against the level of elemental Si in the lens (as inFIG. 2), a similar non-linear polynomial is obtained. For comparativepurposes two separate data points have been inserted into FIG. 2 torepresent current SiH benchmarks, Oasys (% Si=15.0, Dk=104) and Advance(% Si=13.0, Dk=60). By comparing these benchmarks to the data obtainedin Examples 1-11, the addition of silicone microparticles does increasethe Dk of the resulting polymers.

TABLE 2 % Si NP % Si_(Theo) % Si_(Obs) % Water Ex # in Lens of Lens ofLens Content Dk Units 1 0.0 0.0 0 60.5 20 2 2.35 0.9 1 60.0 20 3 4.591.7 2 58.7 ND 4 8.77 3.3 3 58.5 22 5 12.61 4.8 5 58.2 23 6 16.13 6.1 657.6 23 7 19.38 7.4 7 57.5 25 8 22.39 8.5 9 58.5 29 9 25.18 9.6 9 56.931 10 35.00 13.3 13 57.3 34 11 64.3 28.5 24 55.7 76

An SEM micrograph of the lens of Example 10 is shown at FIG. 3. Alllocations imaged by SEM had very rough surfaces containing many clustersof particles. Generally the topography and particle clustering washomogenous throughout the sample (on both sides of the lenses).Individual particle sizes were not able to be measured due to theclustering of the particles. Through observation of SEM images theparticles were estimated to be between about 600 and about 1000 nm insize.

The SEM cross-sections of the lenses looked nearly homogenous to that ofthe surface images, consisting of clustered particles resulting in arough topography.

Examples 12-15 Preparation of Siloxane Nano-Particles Via Free RadicalMicro-Emulsion Polymerization of OHmPDMS and SiMAA DM

Water-soluble initiator, VA-044, was purchased from Wako SpecialtyChemical Company and was also used as received.

Each of the particle dispersions, having the compositions listed inTable 3, were made as follows. Water and DBS were added to a 1 L,3-necked, jacketed reaction flask, equipped with a mechanical stirrerand thermal probe. The water and DBS were heated to 44° C. and stirredunder a nitrogen blanket until a transparent microemulsion was formed.After 30 minutes of stirring at 300 rpm under nitrogen, an aqueousVA-044 solution (200 mg in 1 mL DI water) was added by syringe andallowed to mix. Both OHmPDMS and SiMAA DM were blended together and theresulting mixture was added drop-wise to the microemulsion whilestirring at 300 rpm. After all of the silicone mixture was added (about3-4 hours), the addition funnel was removed and the flask was sealedwith a vented rubber septum. The reaction was kept under a nitrogenatmosphere at 44° C. overnight. The following morning, an additional 200mg VA-044 in 1 mL DI water was added to the microemulsion. Themicroemulsion was then allowed to react for an additional four hours.

Each dispersion listed in Table 3 was characterized via dynamic lightscattering (DLS) with a Malvern-ZetaSizer Nano-S detector. After eachreaction was complete, an aliquot was removed and diluted 10-fold. Thediluted dispersion was then analyzed by DLS to obtain the z-averageparticle size distribution. Measurements were also taken after dialysisof each dispersion. Data files from the DLS were processes usingCUMULANTS analysis function included in the detector software. All datafiles generated good fits within the CUMULANTS curve. The hydrodynamicdiameters of each resulting Silicone ME are listed in Table 4 below withtheir corresponding PDI widths and % PDI values.

TABLE 3 OHmPDMS SiMAA DM H₂O DBS VA-044 Ex. # (g) (g) (g) (g) (mg) 12 2496 350 80 400 13 48 72 350 80 400 14 72 48 350 80 400 15 96 24 350 80400

TABLE 4 Ex. # Z-Avg. D_(H) (nm) PDI Width (nm) % PDI 12 46.7 (0.2) 16.234.7 13 34.8 (0.2) 10.3 29.6 14 44.2 (0.2) 15.7 35.5 15 65.1 (0.2) 35.554.6

The dispersions are stable in water for at least 2 months. Any settlingis readily redispersed with mild agitation.

Dispersions having 50:50 HO-mPDMS and SiMAA DM in water were made asabove. This dispersion was dialyzed against DI water using a 3500 MWCOregenerated cellulose dialysis membrane from Spectrapore. The resultingdispersion was stable for over 2 months.

Frequency histograms of the Examples 12-15 are attached. The data filesgenerated from DLS of Examples 12-15 correlated well using CUMULANTSfit, indicating Gaussian distribution of particle size and evidencinglow or no aggregation in the dispersions. This is shown graphically bythe histograms shown in FIGS. 4-7.

What is claimed is:
 1. A ophthalmic device comprising a hydrogel polymerhaving distributed therein an oxygen enhancing effective amount ofoxygen permeable particles wherein said oxygen permeable particlescomprise hollow nanostructures having an oxygen permeability of at leastabout 200 barrer and average particle size less than about 500 nm in itslongest dimension.
 2. The ophthalmic device of claim 1 wherein saidcomposition has an oxygen permeability of at least about 40 barrer. 3.The ophthalmic device of claim 1 wherein said composition has an oxygenpermeability of at least about 60 barrer.
 4. The ophthalmic device ofclaim 1 wherein said composition has an oxygen permeability of at leastabout 100 barrer.
 5. The ophthalmic device of claim 1, wherein theoxygen permeable particles are non-reactive.
 6. The ophthalmic device ofclaim 1 wherein said oxygen permeable particles have an oxygenpermeability of about 300 barrer to about 1000 barrer.
 7. The ophthalmicdevice of claim 1 wherein said oxygen permeable particles have anaverage particle size of less than about 100 nm.
 8. The ophthalmicdevice of claim 1 wherein said hydrogel polymer has less than 100% hazeand comprises a refractive index from 1.37 to about 1.45, and saidoxygen permeable material has a refractive index within 10% of thehydrogel polymer refractive index.
 9. The ophthalmic device of claim 1wherein said hydrogel polymer has less than 100% haze and said oxygenpermeable material has a refractive index between about 1.37 and about1.45.
 10. The ophthalmic device of claim 1 wherein said hydrogel polymeris selected from the group consisting of homopolymers and compolymerscomprising polyHEMA or PVOH.
 11. The ophthalmic device of claim 1wherein said hydrogel polymer further comprises comonomers selected fromthe group consisting of acrylic acid, methacrylic acid, vinylpyrrolidone, N-vinyl methyl acetamide, N,N dimethyl acrylamide, acrylicacid, glycerol monomethacrylate, MPC (Ishihara monomer), methylmethacrylate, hydroxyethyl acrylate, N-(1,1-dimethyl-3-oxybutyl)acrylamide, polyethylene glycol monomethacrylate, polyethylene glycoldimethacrylate, 2-ethoxyethyl methacrylate, 2-methacryloxyethylphosphorylcholine and mixtures thereof.
 12. The ophthalmic device ofclaim 1 further comprising a % haze of less than about 15%.
 13. Theophthalmic device of claim 1 where said oxygen permeable particles arespherical.
 14. The ophthalmic device of claim 1 wherein said compositionhas an oxygen permeability of at least about 25 barrer.
 15. Theophthalmic device of claim 1 wherein said hollow nanostructures arespherical and have an average particle size of less than about 400 nm.16. The ophthalmic device of claim 1 wherein said hollow nanostructuresare spherical and have an average particle size of about 10-100 nm. 17.The ophthalmic device of claim 1 where the hollow nanostructure comprisea critical pressure of at least 0.05 MPa.
 18. The ophthalmic device ofclaim 1 wherein said hollow nanostructure comprises a critical pressureof at least 0.2 MPa.
 19. The ophthalmic device of claim 1 wherein saidhollow nanostructures comprise a shell surrounding a gas filled space,and wherein said shell at the interface of the gas filled spacecomprises at least one water impermeable material.
 20. The ophthalmicdevice of claim 19 wherein said shell further comprises at least onehydrophilic material encapsulating said at least one water impermeablematerial.
 21. The ophthalmic device of claim 1 wherein said hollownanostructure comprises a gas vesicle protein.
 22. The ophthalmic deviceof claim 21 wherein said gas vesicle protein is encapsulated in apolymer or copolymer comprising repeating units of 2-hydroxyethylmethacryloyl.
 23. The ophthalmic device of claim 21 wherein said gasvesicle protein comprises vesicle walls which are crosslinked.
 24. Theophthalmic device of claim 1 wherein said hollow nanostructure isencapsulated in a polymer or copolymer comprising repeating unitsderived from 2-hydroxyethyl methacrylate.
 25. The ophthalmic device ofclaim 1 wherein said hollow nanostructure is formed from at least onesynthetic material.
 26. The ophthalmic device of claim 1 wherein thehollow nanostructure is formed via emulsion polymerization over atemplate and said template is removed via dissolution after saidnanostructure is formed.
 27. The ophthalmic device of claim 1 whereinthe hollow nanostructure comprises a shell and at least a part of saidshell comprises at least one inorganic component selected from the groupconsisting of metal oxides, boron nitrides, transition metal sulfides,metals, grapheme, perovskite oxide and combinations thereof.
 28. Theophthalmic device of claim 1 wherein said hollow nanostructure arecylindrical with conical endcaps.
 29. The ophthalmic device of claim 1wherein said hollow nanostructures have a shape selected from the groupconsisting of regular or irregular polyhedra, ellipsoids, cones,spheroids and combinations thereof.
 30. The ophthalmic device of claim 1wherein said hollow nanostructures are reactive.
 31. The ophthalmicdevice of claim 1 wherein said hollow nanostructures are crosslinked.32. The ophthalmic device of claim 1, wherein said medical device is acontact lens.
 33. A contact lens comprising a hydrogel polymer havingdistributed in a region outside the optic zone of said contact lens anoxygen enhancing effective amount of oxygen permeable particles whereinsaid oxygen permeable particles comprise hollow nanostructures having anoxygen permeability of at least about 200 barrer and average particlesize less than about 500 nm in its longest dimension.